Structural and functional studies of proneurotrophins

 

TITLE

Structural and functional studies of proneurotrophins

STAFF

D.Lamba

KEYWORDS

neurotrophin, proNGF, SAXS, Intrinsically Unstructured Domain, Surface Plasmon Resonance, antibody binding

COLLABORATIONS
Scuola Internazionale Superiore di Studi Avanzati, Trieste (Italy); Lay Line Genomics S.p.A., Roma (Italy); European Brain Research Institute, Roma (Italy); Scuola Normale Superiore, Pisa (Italy)
DESCRIPTION

NGF (Nerve Growth Factor) is involved in the maintenance and growth of specific neuronal populations, both in the central and peripheral nervous system. NGF, like the other neurotrophins, is translated as a pre-pro-protein. Two splicing variants have been identified, which lead to the formation of two corresponding precursor proteins. Both proteins are glycosylated in vivo, giving rise to a complex scenario where different molecular weight forms could be identified. The signal peptide mediating secretion is cleaved upon translocation into the endoplasmic reticulum. In the trans-Golgi network, the pro-peptide is further processed by furin resulting in the release of the mature neurotrophin. The biological significance of the existence of a long and a short form of proNGF is poorly understood. In vitro, the pro-peptide region, acting as an intra-molecular chaperone, facilitates oxidative folding of recombinant human NGF expressed in E. coli. Conversely, the mature NGF region is strictly required for proNGF to be correctly folded and structurally organized. So far, no structural information on the pro-peptide region has been reported, except that evidences were obtained for an intra-molecular interaction of the NGF pro-peptide region with the mature part. proNGF was found to be the predominant form of NGF in normal brain; its levels increase in the brain of patients affected by Alzheimer's Disease. In cultured neurons, proNGF can induce p75NTR-dependent apoptosis whereas by bind to TrkA can induce neuronal survival, although to a lesser extent than mature NGF. A thorough in vitro biophysical (SAXS, SPR, NMR) and functional characterization, aiming to gain information about the structure and dynamics of proNGF and its likely in vivo role is actively pursued.

Paoletti F, Konarev PV, Covaceuszach S, Schwarz E, Cattaneo A, Lamba D, Svergun DI. Structural and functional properties of mouse proNGF. Biochem Soc Trans (2006) 34, 605.

Paoletti F, Covaceuszach S, Konarev PV, Gonfloni S, Malerba F, Schwarz E, Svergun DI, Cattaneo A, Lamba D. Intrinsic structural disorder of mouse proNGF. Proteins, Structure, Function and Bioinformatics (2009) 75, 990.

CONTACTS

 

Doriano Lamba
Email : doriano.lambaATts.ic.cnr.it
Tel : +39-040-3758514

 

Last Updated (Tuesday, 21 December 2010 17:01)